Field of the Invention
The present invention relates to a method for producing selectively a powder particle comprising the α-form crystal of D-mannitol from a solution containing a water-soluble polymer such as polyethylene glycol (PEG) by using a spray dryer.
Background Art
The spray-drying method is one of the granulation methods, in which a spray dryer is used, and it is a method for drying a solution or a suspension of a pharmaceutical compound, a pharmaceutical additive, or their mixture, as fine liquid droplets, in a chamber within a short time by spraying from a nozzle with small hole diameter with hot air. It is known that powder particles with good fluidity can be obtained by the spray-drying method, and thus it is used as a method for producing not only powders of pharmaceuticals but also carrier particles prepared from inactive pharmaceutical additives such as lactose. The spray-drying method is widely known as a method for producing amorphous dry powder particles. In addition, it also receives attention from the viewpoint of producing particles with various shapes or different surface states and controlling physical properties of obtained particles such as crystal form depending on the solid content in the solution, spray speed, drying temperature, or the like. (see, Non Patent Literature 1, for example).
As a pharmaceutical dosage form in which pharmaceutical particles or carrier particles are used, dry powder inhalants (DPI) are known, for example. DPI is a dosage form to be inhaled as an aerosol of solid particles, which is produced to provide a constant inhalation amount. For solving problems such as adhesion and residuals, for most DPIs, the adhesion property is lowered so that inhalation can be promoted by having a secondary particle formed with an inactive carrier prepared from additives such as lactose. Presently, this is a well used formulation for an adrenocorticosteroidal agent for treating asthma. Furthermore, various inhalants including DPI have been conventionally employed for administration methods for having a local action and avoiding systemic adverse effects, but are also expected to be used as formulations for transpulmonary administration for possibly having a systemic action (see, Non Patent Literatures 2 and 3, for example).
Among the dry powder inhalants (DPI), lactose is known as an inactive carrier (diluent) that is generally used. There is a report in which α-lactose monohydrate is used for DPI (see, Patent Literature 1, for example).
Similar to lactose, D-mannitol as a sugar alcohol is widely used as a pharmaceutical additive. It is known that there are three crystal polymorphs of D-mannitol, that is, β-form (which may be also referred to as modification type I), α-form (which may be also referred to as modification type II), and δ-form (which may be also referred to as modification type III). Each of those three crystal polymorphs including β-form crystal as the most stable crystal, α-form crystal, and δ-form crystal as the most unstable crystal can be produced by a different crystallization method. Melting points and spectrum data such as powder X ray diffraction patterns are known for each of them. However, as commercially available (purchasable) D-mannitol crystals with a single crystal form, there are only the β-form crystal and the δ-form crystal (see, Non Patent Literature 4, for example).
Until now, studies have been made regarding production of crystal polymorphs based on modifications of process parameters such as the spray speed for the spray-drying method (see, Non Patent Literatures 5 and 6, for example).